3-Amino-3-methyl-2-hydroxy-iminobutan-1-ol and salts thereof

ABSTRACT

wherein X is a lower alkyl group or a hydroxymethyl group involving intermediates of formula   WHEREIN Z is lower alkyl or hydroxymethyl is disclosed. A pharmaceutical formulation of a compound of formula (II&#39;&#39;)   wherein Y is a lower alkyl group, in association with a pharmaceutically acceptable carrier, as an antibacterial product, and methods involving the preparation and reductive cyclization of a compound of formula (IV)

United States Patent [1 1 Wood et a].

[ June 17, 1975 [73] Assignee: Burroughs Wellcome Co., Research Triangle Park, NC.

[22] Filed: Feb. 19, 1974 [21] Appl. No.: 443,503

Related US. Application Data [62] Division of Ser. No. l62,297, July 13, 1971.

[52] US. Cl 260/566 A [51] Int. Cl. C07c 131/00 [58] Field of Search 260/566 A, 501.15, 501.17

[56] References Cited OTHER PUBLICATIONS Chem. Abstr. Vol. 62, col. 16,1 13(g) (Grichtel) 1965. Chem. Abstr. Vol. 64, col. l9,470(F) (Grichtel) 1966.

Primary ExaminerLeon Zitver Assistant Examiner-Gerald A. Schwartz Attorney, Agent, or Firm-Donald Brown [5 7] ABSTRACT A pharmaceutical formulation of a compound of formula (II') wherein Y is a lower alkyl group, in association with a pharmaceutically acceptable carrier, as an antibacterial product, and methods involving the preparation and reductive cyclization of a compound of formula HM /NO2 l H2N/ R (Iv) wherein X is a lower alkyl group or ahydroxymethyl group involving intermediates of formula CH I'IOli wherein Z is lower alkyl or hydroxymethyl is disclosed.

4 Claims, No Drawings 3-AMINO-3-METHYL-Z-HYDROXY-IMINOBUTAN- l-OL AND SALTS THEREOF N CH OH HN H N N H CH It has now been found that the compounds represented by the following formula (lI) or their tautomers or pharmaceutically acceptable salts thereof,

wherein Y is a lower alkyl group. preferably one which contains a methylenic group (CH attached to the ring system, are also useful as bacteriostats or in antibacterial products. For instance they produce substantial inhibition of the dihydrofolate synthesis upon which bacteria, such as E. coli, are dependent for their growth, indicating general antagonism of bacterial metabolic processes.

As used herein and throughout the specification, the term lower alkyl group refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms.

The compounds wherein Y is a methyl group is especially preferred.

A compound of formula (11'), or its salt, may also be used in in vitro pharmacological investigations in clinical and diagnostic tests establishing, for instance, the properties of bacteria. When used as a bacteriostat, it is present in a concentration of 110 to 180 mg of base/ml. of the solution in which the organism grows in the absence of the compound. A further use of a compound (11), when in solution, is in the treatment of wounds, for example after surgery, to prevent the growth of bacteria.

If a salt of the compound (W) is used in in vitro or in vivo conditions, the salt should be a salt of a pharmaceutically acceptable acid or alkali, such as hydrochloric acid, sulphuric acid, tartaric acid, maleic acid, ammonia, sodium hydroxide and tetramethyl ammonium hydroxide.

According to one aspect of the present invention there are provided pharmaceutical formulations comprising the compound (Il') or tautomeric forms thereof, or pharmaceutically acceptable salts thereof, in association with a pharmaceutically acceptable carrier.

The substance may be presented advantageously in discrete units, such as tablets, capsules, cachets or ampoules, each containing a predetermined amount of the compound. It may also be presented as a powder or granules as a solution or suspension in an aqueous or non-aqueous (optionally emulsified) liquid, or as an ointment. For parenteral use, the formulations must be sterile and are presented in sealed containers. The formulations of this invention may be made by any of the methods of pharmacy, and may include one or more of the following accessory ingredients: diluents, solutes, buffers, flavouring, binding, dispersing, surface-active, thickening, lubricating and coating materials, preservatives, antioxidants, and ointment bases, and any other acceptable excipients.

The above-mentioned lowest member of the group of compounds (ll'), the 6-methyl-substituted compound, has been prepared according to the method described by Pfleiderer and Zondler (Chem. Ber. 1966, 99, 3008), in which 3-amino-3-methylbutan-2-one hydriodide is reacted with 2-amino-4-chloro-6-hydroxy-5- nitropyrimidine and the product reductively cyclised. However the preparation of the amino ketone is cumbersome, involving the formation of an undersirable and potentially explosive azide intermediate derivative. The amino ketone preparation is therefore expensive, and the final stages of the entire process are unsatisfactory in many respects, in particular the amino ketone undergoes self condensation and a number of side products are produced, with concomitant low yield of the desired pteridine.

A much improved method of synthesis of the compounds of formula (11),

wherein Z is a lower alkyl group, preferably one which contains a methylenic group attached to the ring system, or a hydroxymethyl group, has now been discovered which uses the intermediate of formula (IV) or, going one stage further back, that of formula (V). The compounds (ll) can therefore be prepared according to the following reaction sequence:

Continued fecting reductive cyclisation of the former. This may be achieved by the use of reducing agents which are capable of reducing the nitro group without attacking other parts of the molecule; for example it may be achieved readily by means of catalytic hydrogenation using catalysts such as palladium charcoal, platinum, or Raney nickel, but reduction with sodium dithionite is espe- The compound (V) or a salt thereof can be prepared by reacting a nitroso halide, for practical purposes most preferably the chloride, of formula (VI) with ammonia solution. Conveniently ammonia gas is bubbled through the reaction solvent, which may be an alkanol such as methanol, thereby preventing any precipitation during the process. The compund (VI) can in turn be prepared by an addition reaction with the appropriate nitrosyl halide, e.g. nitrosyl chloride. The reagent may be available commercially or could conveniently be prepared in situ, for instance, from a nitrosating agent with a concentrated hydrohalic acid. Suitable nitrosating agents include isoamyl nitrite and methyl nitrite.

cially preferred. This latter reagent is cheap, effects a rapid reaction and does not require a source of hydrogen as do the catalytic reagents. The reductive cyclisation may be carried out under a variety of conditions, the pH of the medium required depending on the choice of reducing agent. An alkaline medium is preferred for reduction with sodium dithionite and also for hydrogenation using Raney nickel.

Another manner of carrying out the above reductive cyclisation to prepare compound (II) proceeds through the isolation of the ketonic intermediate for formula Preparation of the novel pyrimidine ketoxime (IV) is readily effected by reacting the compound of formula (V) or a salt thereof with readily-available 2-amino-4- halogeno-6-hydroxy-5-nitro pyrimidine. The halogeno substitutent is a bromine, iodine or fluorine atom or most preferably a chlorine atom, and an acid addition salt of the compound (V) may conveniently be a hydrohalide, preferably the hydrochloride. The reaction is desirably effected in the presence of an acid binding agent such as a weak base, for example sodium carbonate, sodium acetate, or in particular a tertiary amine,

such as triethylamine.

In formulae (VII) and (VI), the definition of X is the same as that defined herein for Z, except that X may also be an ester group, such as an acyl ester CH O.- COR, where R is a lower alkyl group. The sequence (VII) to (V) is especially applicable when X is a hydroxymethyl group.

The intermediates of formula (VI) are novel compounds, except when X is a methyl group, and form yet a further aspect of the present invention.

There are many ways of preparing compound (VII) wherein X is a hydroxymethyl group or an ester thereof, but it has been found advantageous and convenient to proceed:

a. when X is hydroxymethyl (VII) either i. by reduction of the corresponding acid (IX) with a powerful reducing agent, especially an organo metallic hydride, such as lithium aluminiumhydride, or preferably sodium dihydro-bis-2- methoxyethoxy aluminate; or

ii. by structural rearrangement of 3-methyl-3- hydroxybut-l-ene of formula (VIII) to the thermodynamically more stable alcohol of formula (VII'), for example by means of boric acid;

b. when X is an acyl ester group, such as CI-I O.- COR. either i. by reaction of the alcohol of formula (VII) with CH3 CH CH C=CHCO H c= CIT-C1120 CCI-i=-Cil 3 CH on (VII') l (VIII) c=cncn ocon CH 3 tvrr") Compound (VII") may then be converted with a niamino group is protected to give compound (XII), the trosating agent, as hereinbefore defined, to the nihydroxyl group is oxidised, for example using chrotrOSOhfllide 0f i Which may be further remium trioxide in pyridine, to produce compound (XI), acted to g e mpo n of formula or 8 Salt and finally the protecting group is removed by hydrolyt e e Z iS a hydroxymethyl group. The sesis, conveniently using a mineral acid. The protection quehce i0 t0 is especially Preferred of the amino group is readily achieved using an acyl for the initial Stages of the syhthesisgroup, such as a benzoyl, acetyl or carbobenzoxy The compound of formula (V) or a salt thereof may group, f bl h benzoy] group also he p p from the corresponding ketohe of According to the present invention is further aspects mula (X) or a salt thereof, wherein Y is a lower alkyl there are also provided; group preferably which contains a meth ylemc l. The methods described herein for preparing any of group atteched to e ring System, by reaction with the compounds of formula (II), comprising effecting droxylamme or an acid salt thereof. Advantageously at reductive cyclisation of compounds of formula (IV) least one equivalent of sodium acetate, sodium carbon- The methods described herein for preparing any of ate or triethylamine is present to act as an acid binding the compounds (IV) from (v) (V) from (VI) or (VII), agent" (V) from (X) and (X) from (XIII).

3. Compounds of formula (II), (IV), (V), (VI), and (X), whenever prepared by a method as defined under H H l: (1), (2) or (3), respectively. I

2 l 2 I ll 4. As novel compounds of value as chemical interme- CH 3 (m NOH dimes:

Compounds of formula (XI), as hereinbefore de- (X) (v) fined, especially 3-N-benzoylamino-3-methybutan- 2-one.

The following examples illustrate the invention but are in no way intended to limit the scope of the invention.

Temperatures are in degrees Celsius.

Compound (X) may itself be prepared, for example, according to the following reaction scheme:

(m C11 1'! I o N-c II Y.CHO- o ucc Y a EXAMPLE 1 CH3 CH3 Oil Synthesis of Compounds of Formula (V) (XIV) l. 3,3-dimethyl allyl alcohol (VII') X=Cl -I OH) a. A solution of 3,3-d1methylacryl1c acid (20 g., CH H CH H 0.2M) in sodium-dried ether (200 ml.) was treated 3 i i 3 dro wise ith 64 (O 2M+l07) f 707 1 ton of H NC c-Y -7- acorm-c- C-Y P Y 0 0 3 F a i i sodium dihydro-bis (Z-methoxyethoxy) alummate in cm on 3 3 benzene, the temperature being maintained at 0 until the addition was complete (about 1 hour). The reac- (XIII) (XII) tion mixture was stirred for five hours at room temperature, and water was then added slowly. The sodium aluminate which precipitated was filitered off, and the fil- CH 3 trate was extracted with ether (4 X 100 ml.) The com- 3 i rz'cormc co-Y H2N-C -coy bined extracts were dried, the solvent was removed,

l and the residual oil was distilled to give 3,3- 3 3 dimethylallyl alcohol as a colourless liquid b.p.

5455/25 mm Hg. (x1) (x) or b. A mixture of 3-methyl-3-hydroxybut-l-ene (64 g.) wherein Rl is an alkyl, y i' pand boric acid (60 g.) was stirred at 1 10C in an appa- Nitiopropahe, which is readily available, 15 e011- ratus equipped for distillation. The substituted butene dehsed with the pp p aldehyde effoi'mhla distilled of gradually over 5 hours and was replaced in the presence Of a t g b c catalyst Such as an 65 with a fresh supply at intervals throughout the 5 hours kali metal hydroxide o alkOXide- The PrOdllCt The cooled reaction mixture was diluted with water, is reduced, for example by cat ly ic hy r gena ion, neutralised with solid sodium carbonate and extracted preferably using Raney nickel, to compound (X the with ether. The ethereal extracts were brine washed,

dried and evaporated and the residual oil distilled (13 g.) 50-60/14 mm Hg.

2. 3,3-dimethyl allyl acetate (VII") (X=CH O.- CO.CH

a. 3,3-dimethylallyl alcohol (4.3 g., 0.05 M) and acetic anhydride (6.5 g., 0.07 M) were heated on a steam bath for 1 hour and them distilled from the same flask at water pump pressure. The total distillate was poured onto ice-water and the pH adjusted to 7.0 with sodium hydroxide, under ether. The ethereal layer was removed and the aqueous solution extracted with ether (2 X 20 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a pale yellow oil. Fractional distillation gave the 3,3 dimethylallyl acetate as a colurless oil (3.5 g.) b.p. 4043/20 mm Hg.

b. A mixture of 3-methyl-3-hydroxybut-l-ene (32 g.), acetic acid (150 ml.) and boric acid (30 g.) was stirred at 105 for 4 hours. The cooled reaction mixture was diluted with water, neutralised with solid sodium carbonate and extracted with ether (3 X 50 ml.) The combined ethereal extracts were brine washed, dried and the solvent removed giving a pale yellow oil (30 g,) Distillation gave 3,3-dimethylallyl acetate as a colourless oil (22 g.) b.p. 4445/14 mm Hg.

3. 3-chloro-3-methyl-2-nitrosobutan-1-ol (X=CH OH) 3,3-Dimethylallyl alcohol (50 ml), iso-amyl nitrite (70 ml. and glacial acetic acid (100 ml.) were cooled in an ice-salt bath and treated with ice-cold concentrated hydrochloric acid (40 ml) added dropwise with stirring. Glacial acetic acid (40 ml) was added slowly maintaining the temperature at 5. Towards the end of the addition a white solid precipitated. The reaction mixture was then stirred at 0 for a further 30 minutes and cooled in an acetone/CO bath for 15 minutes. The product was filtered through a large precooled Buchner funnel and washed with a little cold benzene and dried. Recrystaliisation from dioxan gave the desired nitrosobutanol as colourless needles (19 g.) m.p. 119.

4. 3-chloro-3-methyl-2-nitroso-l-butyl acetate (Vl) (X=CH O.CO.CH

3,3-Dimethylallyl acetate (25 ml.), iso-amyl nitrite (45 ml.) and glacial acetic acid (65 ml.) were cooled in an ice-salt mixture. An ice-cold mixture of concentrated hydrochloric acid (20 ml.) and glacial acetic acid (20 ml.) was added gradually with stirring. The solution became green and towards the end of the addition a white solid precipitated. The solid was collected by filtration and dried (13 g.) Recrystallisation from CCl 40/60 petrol gave the title compound as colourless needles (10 g.) m.p. l17-119.

5. 3-chloro-3-methyl-2-nitrosobutane (Vl) (X=CH A mixture of 2-methylbut-2-ene (70 g.) and iso-amyl nitrite (100 ml.) was stirred in an ice-salt bath for 30 minutes and then concentrated hydrochloric acid 100 ml.) was added dropwise with stirring at such a rate as to keep the temperature below (-l hour) A blue solution was obtained, and a crystalline paste gradually formed. The reaction mixture was stirred for a further 30 minutes below 5C, followed by cooling in an acetone/CO bath for fifteen minutes. The pale blue precipitate was filtered and washed with ice-cold ethanol (50 ml.) The product was dried in a stream of air until all traces of blue colour had gone, leaving the title compound as colourless crystals (60g.) m.p. 75.

6. 3-amino-3-methyl-2-hydroxyiminobutan-l-ol hydrochloride (salt of V) (Z=CH OH) a. 3-Chloro-3-methyl-2-nitrosobutan-l-ol 10 g.) was dissolved in dry methanol (200ml.) saturated with ammonia at 0. The mixture was then left overnight at room temperature and evaporated to dryness in vacuo at room temperature. The residue was extracted with hot dry benzene (200 ml.) and the benzene-insoluble component extracted further with hot secondary butanol (220 ml. The secondary butanol extract was evaporated to small volume and the product precipitated by dropwise addition of ether. This was filtered and dried in vacuo (7.5g.)m.p. 172l73.

b. 3-Chloro-3-methyl-2-nitroso-l-butyl acetate (5 g.) was treated with a methanolic ammonia solution (15 ml) and the mixture stirred at room temperature in a sealed flask for 2 days. Removal of the volatile material gave an oily solid which was triturated with ethanol and the soluble component retained. Removal of the ethanol gave a residual solid which was triturated with hot acetone giving a creamy white powder (4 g.) m.p. 178179 7. 3-amino-3-methylbutan-2-one oxime hydrochloride (Salt of V) (Z=CH 3-Chloro-3-methyl-2- nitrosobutane (60 g.) was added portionwise to dry methanol (600 ml.) saturated with ammonia at 0. The solution was left at room temperature for 5 hours then refluxed for 16 hours in the presence of a stream of dry ammonia. The mixture was evaporated to dryness in vacuo at room temperature and the residue extracted with hot dry benzene (900 ml.) followed by boiling secondary butanol (1300 ml.). The secondary butanol extract was evaporated in vacuo at room temperature to a thick slurry. This was cooled, filtered and dried in vacuo (56 g.) m.p. 190 (decomp).

EXAMPLE 2 Alternative Synthesis of Compounds of Formula (V) 1. 3-nitro-3-methylbutan-2-ol (XIV) (Y=CH Freshly distilled acetaldehyde (27.3 g., 0.62 M) was added portionwise to a well stirred solution of 2- nitropropane (52.08 g. 0.62 M) in ethanol (30 ml.) and ION sodium hydroxide (1.2 ml.), maintaining the reaction temperature at 3035. After two-thirds of the aldehyde had been added, a further 1.2 ml. of ION sodium hydroxide and 8 ml. of water was added followed by the remaining acetaldehyde, and the mxiture stirred at room temperature for 4 days. Excess acetaldehyde and 2-nitropropane were removed at the water pump. The residue was dissolved in water (ml) and extracted with ether (3 X 50ml.). The combined ethereal extracts were brine washed, dried and distilled to give the title compound as a colourless oil (26g) b.p. 82-83/14 mm Hg.

2. 3-amino-3-methylbutan-2-ol (XIII) (Y=CH 3-Nitro-3-methylbutan-2-ol (5g.,0.035 M) was dissolved in methanol (300 ml.) and hydrogenated over freshly prepared Raney nickel (-2g) at room tempera ture and 4 atmospheres pressure for 5 hours until there was no further visible uptake of hydrogen. The nickel catalyst was removed by filtration and the solvent evaporated to give the title compound as a colourless oil (XII) 3-Amino-3-methylbutan-2-ol (6.1 g.) was dissolved in benzene (120 ml.), treated with anhydrous sodium carbonate (16 g.) and cooled to 10. The mixture was then treated with benzoylchloride (9.2 g.) in benzene (30 ml.) at 10 and left to stand at this temperature for 3 hours. After a further 2 hours at room temperature the reaction mixture was refluxed for 30 minutes, filtered hot and the solid extracted with hot benzene (2 X 100 ml. The combined filtrates were evaporated to 100 ml. and cooled. The colourless crystalline solid was collected and recrystallised from benzene as colourless needles (5g.) m.p. ll8-l20.

4. 3-N-benzoylamino-3-methylbutan-2-one 3) 3-N-Benzoylamino-3-methylbutan-2-ol (2.02g., 0.1 M) in anhydrous pyridine (4 ml.) was added to the oxidising reagent, prepared by adding chromium trioxide (3 g., 0.03 M) to a vigorously stirred, cooled solution of pyridine (35 ml.) over 15 minutes. The mixture was stirred at for 30 minutes and then at room temperature for 22 hours. The reaction mixture was poured onto water (100 ml.) and extracted with ether (3 X 50 ml.) The combined extracts were washed with brine, dried and evaporated to give a white powder, which recrystallised from benzene-petrol as colourless needles (1.6g) m.p. 124l25.

5. 3-amino-3-methylbutan-2-one-hydrochloride (Salt of X) (Y=CH 3-N-Benzoylamino-3-methylbutan-2-one 1g.) was suspended in 20% hydrochloric acid (10 ml.), refluxed for 8 hours, cooled and the precipitated benzoic acid filtered. The filtrate was evaporated and the'residue treated with water (2 ml.) and filtered to remove a further quantity of benzoic acid. The resultant fitrate was evaporated and the residue triturated with cold ethanol (3 X 5 ml.) filtering, evaporating the filtrate and discarding the solid each time. The resultant residue was recrystallised from ethanol-ether as colourless needles (500 mg. m.p. 212-2l4. I

This was then reacted with hydroxylamine in the presence of triethylamine to give 3-amino-3- methylbutan-2-one oxime hydrochloride (Salt of V) EXAMPLE 3 Synthesis of Compounds of Formula (ll) 1. 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine 2-Amino-4-chloro6-hydroxypyrimidine (7.5 g.) was dried over P 0 at 0.5 mml-lg for 2 hours, partially dissolved in concentrated sulphuric acid (9 ml.) and the slurry cooled to 0C and treated portionwise with fuming nitric acid (8 ml.) with constant stirring. The yellow solution was stirred for an additional 30 minutes at room temperature and then poured onto ice (30 g.). The pale yellow solid was filtered, washed with icewater and then ether and dried over P 0 at 0.5 mmHg giving the title compound as a pale yellow solid (8.32 g.) m.p. 260 (decomp.)

2. 2-amino-4-( l,1'-dimethyl-3- hydroxyacetonyl)amino-6-hydroxy-5-nitro pyrimidine oxime (lV) (Z=CH OH) 3-Amino-3-methyl-3-hydroxyiminobutan -1-o1 hydrochloride (2.5 g.) was dissolved in ethanol (16 ml.) and treated with 2-amino-4-chloro-6-hydroxy-S-nitropyrimidine (2.8 g) and triethylamine (2.8 g.), and the mixture stirred at room temperature for 2 hours, at reflux for 4 hours and at room temperature for a further 8 hours. The reaction mixture was heated, filtered hot and the solid washed with hot ethanol. The ethanol was removed from the combined filtrates giving a pale yellow powder which was triturated with small amounts of ethanol. The powder was recrystallised from boiling water to give the title compound as an off-white powder (1.5 g).

3. 2-amino-4-( l ,1-dimethylacetonyl)amino-6- hydroxy-S-nitro-pyrimidine oxime (lV) (Z=CH 3-Amino-3-methylbutan-2-one oxime hydrochloride (5 g.), 2-amino-4-chloro-6-hydroxy-5-nitro pyrimidine (6 g.) and triethylamine (10ml.) were refluxed in ethanol (200 ml.) for 16 hours. The reaction mixture was cooled and the white precipitate was collected and purified by dissolving in ZN-ammonium hydroxide solution. Reprecipitation with glacial acetic acid gave the pyrimidinylamino-ketone oxime as a white solid (6.0 g.) m.p. 260 (decomp).

4. 2-amino-4-(1',l'-dimethyl-3- hydroxyacetonyl)amino-6-hydroxy-5-nitr0 pyrimidine (llI) (Z=Cl-l Ol-l) 2-Amino-4-(1 ,1 -dimethyl-3 -hydroxyacetonyl) amino-6-hydroxy-5-nitro pyrimidine oxime (2 g.) was dissolved in 2N hydrochloric acid (200 ml.) and the solution heated on a steam bath for 2 hours. The reaction mixture was concentrated by rotary evaporation at 0.5 mm Hg. at 40 and the resultant solid triturated with acetone, filtered and dried. The yellow powder was recrystallised from boiling water as an off-white powder 5. g 2-amino-4-( l l -dimethylacetonyl )amino-6- hydroxy-S-nitro pyrimidine (lll) (Z=CH 2-Amino-4-( l,1'-dimethylacetonyl)amino-6- hydroxy-S-nitro-pyrimidine oxime 6.0 g.) was hydrolysed by refluxing for 10 minutes with 2N-hydrochloric acid. The reaction mixture was cooled, filtered and neutralised with 0.880 ammonium hydroxide to precipitate the pyrimidinylamino-ketone as a colourless crystalline solid (5.0 g.) m.p. 289.

6. 2-amino-4-hydroxy-6-hydroxymethyl-7,7- dimethyl-7,8-dihydropteridine (ll) (Z=CH OH) 2-Amino-4-( l ',1'-dimethyl-3 hydroxyacetonyl)amino-6-hydroxy-5-nitropyrimidine (4 g.) was suspended in water (50 ml.), heated on the steambath, and treated with solid sodium dithionite until the original solid has dissolved. After 5-10 minutes the solution was cooled, whereupon the off-white product began to separate out. This was completed by the addition of 0.880 ammonia to pH 8.5-9.0 (2.1 g) m.p. 300.

In another experiment the pyrimidinylamino ketone was dissolved initially in 0.1N sodium hydroxide followed by portionwise addition of sodium dithionite and isolation of the product (1.6 g.)

7. 2-amino-4-hydroxy-7-8-dihydro-6,7,7- trimethylpteridine (ll) (Z=CH 2-Amino-4-( l ',l -dimethylacetonylamino)-6 hydroxy-S-nitropyrimidine (2 g.) was dissolved in dilute ammonium hydroxide, the solution warmed gently and soldium dithionite added portionwise until a colourless solution was obtained. The pH was adjusted to 7 with acetic acid and the dihydropteridine which precipitated was filtered and washed with water, ethanol and ether (1.75 g.) m.p. 298300.

8. 2-amino-4-hydroxy-6-hydroxymethyl-7,7- dimethyl-7,8-dihydropteridine (ll) (Z=Cl-l OH) Direct Method 2-Amino-4-( l ',l -dimethyl-3 -hydroxyacetonyl) amino-6-hydroxy-5-nitro pyrimidine oxime (50 mg.) was dissolved in 0.1N sodium hydroxide (3ml.) with warming on a steam bath. The warm solution was treated portionwise with sodium dithionite until the yellow colour was discharged On cooling a white solid precipitated which was washed with water and dried giving the title compound as a pale yellow powder (40 mg.)

9. 2-amino-4-hydroxy-7,8-dihydro-6,7,7-trimethyl pteridine (II) (Z=CH Direct Method 2-Amino-4-( l ,1 -dimethylacetonylamino)-6- hydroxy-S-nitropyrimidine oxime (50 mg.) was dissolved in 0.1N sodium hydroxide (3 ml.) with warming on the steam bath. The warm solution was treated with sodium dithionite until the yellow colour was discharged. This was collected, washed with water and dried to give the title compound as a pale yellow powder (35 mg.).

Example 4 Tablet containing a compound. (ll) (a) 'lngredients 2-Amino-4-hydroxy-7,8-dihydro (b) Procedure The pteridine (ll), microcrystalline cellulose and starch were granulated with a solution of the methylhydroxyethylcellulose in 50% aqueous ethyl alcohol. The magnesium stearate was added to the dried granules, and the whole then compressed.

Example 5 Ointment containing a compound (ll) (a) Ingredients 2-Amino-4-hydroxy-7,8-dihydro- 2 g. 6,7,7-trimethylpteridine (ll) White soft paraffin 100 g.

-Continued Example 4 Tablet containing a compound. (ll) (b) Procedure The pteridine (ll) was incorporated in part of the white soft paraffin which had been softened by heat. The rest of the white soft paraffin was added, and the whole throughly mixed.

What we claim is: 1. A compound [of formula. (V)

[where Z is hydroxymethyl] 2. An acid or alkali salt of the compound of claim 1 wherein the acid or alkali is selected from the group consisting of hydrochloric acid, sulfuric acid, tartaric acid, maleic acid, ammonia, sodium hydroxide and tetramethyl ammonium hydroxide.

3. A hydrohalide salt of the compound of claim 1.

4. A hydrochloride salt of the compound of claim 1.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION 8 PATENT N0. 3, 9 ,3 7

DATED JUNE 17 1975 INVENTOMS) 1 HAMISH CHRISTOPHER SWAN woon, ET AL.

it is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

COLUMN 2, lines 60-65, please delete (3H [H N i: c z

NOH

-- and rewrite as follows 3 H N T Z NOH UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. :3,890,387 5 DATED E 17 1975 |NVENTQR(5) HAMISH CHRISTOPHER SWAN WOOD, ALA,

it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

COLUMN 12, lines 10-29, claim 1, please delete the present claim 1, and rewrite as follows:

Claim 1. A compound 3 H N C C CH OH 2 (3H tiOH 3 Signed and Scaled this ninth Day of December 1975 [SEAL] Attest: 5

RUTH C. MASON C. MARSHALL DANN Arresting Offit Commissioner oj'Parenrs and Trademarks 

1. A COMPOUND
 2. An acid or alkali salt of the compound of claim 1 wherein the acid or alkali is selected from the group consisting of hydrochloric acid, sulfuric acid, tartaric acid, maleic acid, ammonia, sodium hydroxide and tetramethyl ammonium hydroxide.
 3. A hydrohalide salt of the compound of claim
 1. 4. A hydrochloride salt of the compound of claim
 1. 